1alpha, 11alpha-epoxy steroids and process



United States Patent 3,296,254 111,110t-EPOXY STEROIDS AND PROCESS George B. Spero, Kalamazoo, Mich., assignor to The Upjohn Company, Kalamazoo, Mich., a corporation of Delaware No Drawing. Filed Jan. 31, 1962, Ser. No. 170,275 20 Claims. (Cl. 260-23955) This invention relates to novel 1a,l1aepoxy steroids and to processes for the production thereof.

Some of the novel compounds of this invention are represented by the following formulae:

and

wherein R and R are selected from the group consisting of hydrogen and methyl in which when R is methyl R is hydrogen, R is selected from the group consisting of hydrogen or the acyl radical of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inclusive, and Z is selected from the group consisting of CH CH OR OOH; (a) 41:0;(0) =0 and (0)11 0 3H b-OH 0-0-0 in which R is defined as above.

In this application, the wavy line appearing at the l6-position indicates the on (alpha) configuration, the [3 (beta) configuration or mixtures thereof.

The novel 1a,l1a-epoxy compounds of this invention are useful intermediates in the preparation of therapeutically important l-dehydrocorticoids, e.g., prednisone, prednisolone, dexamethasone, medrol (6-methylprednisolone) 16a-methylprednisolone and the like. The novel process of this invention constitutes a new approach to the production of l-dehydrocorticoids. 1,2-double bond has been introduced either by bromination and dehydrobomination or by dehydrogenation with selenium dioxide or microbiological methods.

The process of this invention comprises treating an 11- hydroxy compound of the androstane or the pregnane series, containing no other free hydroxyl groups, with a metal acylate having oxidizing action to produce the corresponding 1a,11a-epoxide. The epoxy group is then opened with an acid or a base to produce the corresponding A -lla-hydroxy steroid.

Heretofore the v Starting materials for the process of the present invention are ll-hydroxy compounds of the pregnane and androstane series which can also contain further substituents in the ring system and in the side chain, more especially in one or several of the 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 15, 16, 17, 18, 19, 20, 21 and 22-position-s such as for example esterified or ethen'fied hydroxyl groups, free or ketalized oxo groups, esterified carbonyl groups, lower-alkyl groups e.g., methyl, ethyl, propyl and the like or halogen atoms and which can also contain one or more double bonds in the ring system and in the side chain, e.g., 5, 6, 15, 16, 17 (20) and the like.

Typical starting materials including llu-hydroxyprogesterone bis alkylene ketal, 11a-hydroxy-6a-methylprogesterone bis alkylene ketal, 11a-hydroxy-16a-methylprogesterone bis alkylene ketal, 11a-hydroxy-16B-methylprogesterone bis alkylene ketal, lower-alkyl Ila-hydroxy-4,17(20) [cis] pregnadien-3-one-21-oate alkylene ketal, lower alkyl 11a-hydroxy-6-methyl-4J7(20) [cis]- pregnadien-3-one-21-oate alkylene ketal, lower.-alkyl 11mhydroxy-16a-methyl-5,17(20) [cis] pregnadien-3-one-21- oate alkylene ketal, loWer-alkyl 11a-hydroxy-16fi-methyl- 5,17(20) [cis] pregnadien-3-one-21-oate alkylene ketal, llot-hydroxypregnenolone 3-acylate, lloc-hYdIOXY-16amethyl pregnenolone 3-acylate, lla-hydroxy-6-methylpregnenolone 3-acylate, 11ot-hydroxy-4-androstane-3,17- dione bis alkylene ketal, 1la-hydroxy-5a-pregnane-3,20 dione bis alkylene ketal, the corresponding llfl-hydroxy compounds of those listed above, 17:20, 20:21-bismethylenedioxy-l LB-hydroxy 4 pregnen-3-one alkylene ketal, 17:20,20:21-bismethylenedioxy l1B-hydroxy-6u-methyl- 4-pregnen-3-one alkylene ketal, 17:20,20:21-bismethylenedioxy-11B-hydroxy 16a methyl-4-pregnen-3-one 3- alkylene ketal, 17:20,20:21 bismethylenedioxy-llB-hydroxy-l6 3-methyl-4-pregnen3-one alkylene ketal and the like. Many of the above listed compounds are known in the art, the others are prepared in accordance with preparations 1 through 10 contained herein.

The process for the preparation of the ladle-epoxy compounds of this invention is illustratively represented by the following reaction schemes:

wherein R and R have the meanings previously given, R is an alkylene radical containing not more than 8 carbon atoms, inclusive, and the attaching oxygen to carbon bonds are separated by a chain of at least 2 and not more than 3 carbon atoms, e.=g., ethylene, 1,2-propylene, 1,3- propylene, 2,3-butylene, 2,4-amylene, 4-methyl-1,2-amylene, 6-methyl-1,4-hexylene, 1,2-'heptylene, 3,4-heptylene,

Patented Jan. 3, 1967 1,3-octylene, etc., X is selected from the group consisting of the a-hydroxyrnethylene radical and the ,B-hydroxymethylene radical Z is selected from the group consisting of:

CH COOR 112 O (b) H d H C a i/ an (e) z O G O I 0 CH3 CH C-O in which R is defined as above and R is a lower alkyl radical, containing from 1 to 8 carbon atoms, inclusive, and Z is selected from the group consisting of on, 0003 o-OH: (a) i=0;(b) 11 and (0) H in which R is defined as above.

wherein Ac is the acyl radical of an organic carboxylic acid preferably a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inclusive, R, R R and X have the same meanings as meaning previously given.

The ladle-epoxidation process comprises: treating an ll-hydroxy steroid of the androstane or pregnane series containing no other free hydroxy groups, e.g., the compounds of Formulas IA and B with a lead tetraacylate in which the acyl radical is that of a lower aliphatic or aromatic acid, for example, lead tetraacetate, lead tetrapropionate, lead tetrabutyrate, lead tetrabenzoate and the like to produce the corresponding 10,11a-6POXY compounds of Formulas 11A and HE. The reaction is carried out in a non-polar solvent which is inert to the oxidizing agent, e.g., eyclohexane, methylcyclohexane, dirnethylcyclohexanes, benzene, toluene and the like. The reaction is conveniently carried out'at the reflux temperature oi the reaction mixture although higher or lower temperatures can be used, e.g., a temperature between 50 degrees Centigrade and the boiling point of the reaction mixture. The reaction is continued until the re- 5 action is essentially complete. The reaction time de: pends on the solvent employed and the temperature at which the reaction is carried out. The 1a,11a-epoxide is recovered from the reaction mixture by conventional methods, e.g., chromatography and/or crystallization,

from a suitable solvent. The 3-ketal and 3,20-bisketal compounds of Formula IIA can be hydrolyzed by known methods for hydrolyzing cyclic ketal groups, e.g., dilute sulfuric acid as disclosed in U.S. Patents 2,707,184, 2,758,-

993, and 2,968,655 to give the corresponding 3 and 3,20-

diketo compounds of Formula IIIA.

The 3-acylates of Formula IlB can be hydrolyzed to the corresponding 3-hydroxy compounds (IIB) in accordance with known methods for hydrolyzing 3-acylate groups to free alcohols, e.g., pregnenolone acetate to pregnenolone. The free hydroxy compounds of Formula HB can then be oxidized at the 3-position by known methods, e.g., with an N-haloamide or an N-h-aloimide in pyridine, with chromic anhydride or chromium trioxide and dilute sulfuric acid in an organic solvent, e.g.,

and glacial acetic acid, or other known oxidizing agents to produce the corresponding 3-keto compounds of Formula IIlB.

Compounds of the androstane series can also be converted to the corresponding la,lla-epoxides, e.g., llahydroxy-4-androstene-3,ZO-dione bis alkylene ketal or the corresponding llfi-hydroxy compound can be converted to 111,11a-epoxy-4-androstene-3,20-dione bis alkylene ketal with a lead tetraacylate in accordance with the process described, above, followed by deketalization by known methods, e.g., hydrolysis with sulfuric acid to produce 10:,1lm-epoxy-5-androstane-3,20-dione, an active anabolic androgenic agent having cholesterol lowering activity.

The novel 4,l7(20)-pregnadienes of Formula IlA(a), can be converted to the corresponding compounds having the full cortical side chain in accordance with procedures well-known in the art. The process is repre. sented by the following reaction scheme:

acetone, or methylene chloride, with sodium dichromate wherein Ac, R, R, R R 'and R have the same meanings as previously given.

The conversion of the compounds of Formula IC to the compounds of Formula VC can be accomplished in accordance with methods known in the art for converting 21-esters to the adrenal cortical hormone side chain. The 21-carboxylic acid ester group of Formula is first reduced with lithium aluminum hydride (U.S. Patent 2,707,- 184) to produce the corresponding 21-hydroxy compound (IIC), which is then esterified with an acylating agent in accordance with methods known in the art, e.g., the preparation of hydrocortisone acylate from hydrocortisone, for example with the acid chlorides, bromides, and anhydrides of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inclusive, to produce the corresponding 21-acylate (IIIC). The thus-produced ester is then oxidatively hydroxylated with osmium tetroxide and an oxidizing agent, e.g., hydrogen peroxide, an organic peracid, an amine oxide peroxide, or an aryl iodo oxide, in the manner described in U.S. Patent 2,769,823, 2,769,825, or Hogg et al., J. Am. Chem. Soc., 77, 4436 (1955); to produce the corresponding 17a-hydroxy-20-keto-2l-acyloxy compound IVC, which can be hydrolyzed with base, e.g., sodium methoxide, sodium hydroxide, sodium bicarbonate in methanol, preferably while purging with nitrogen to produce the corresponding 2l-hydroxy compound (IVC). The 3-ketal group can be removed either before or after hydrolysis of the 2l-acylate in accordance with the method heretofore described for hydrolyzing cyclic ketal groups, e.g., using dilute sulfuric acid, to produce the corresponding 3-keto compounds of Formula VC.

The la,11u-epoxy-3-keto compounds of Formula A and BB, above, are easily converted with an acid or a base to the corresponding A -11a-hydr0xy compounds of the following formula:

lay-( it if wherein R, R and Z have the same meanings as previously given. The oxide opening is carried out by heating the selected ballot-EPOXY compound of Formula A in an organic acid such as glacial acetic acid, propionic acid, butyric acid and the like or with a mineral acid, e.g., hydrochloric acid, sulfuric acid, phosphoric acid, etc., in the presence of a suitable organic solvent such as ethanol, methanol, propanol, acetone and the like, or the epoxide opening can be preferably carried out under basic conditions for example by dissolving or suspending the selected 1a,11a-epoxide in a suitable organic solvent, e.g., ethanol, methanol, propanol, butanol, acetone, dioxane, etc., and treating the reaction mixture with a base, for example with an alkali metal salt of an aliphatic carboxylic acid, such as sodium acetate, potassium acetate, sodium propionate and the like; alkali metal alcoholates, bicarbonates, carbonates, and hydroxides, e.g., sodium methylate, sodium bicarbonate, potassium carbonate, sodium hydrox- 6 ide and the like to produce the corresponding A -1lu-hydroxy compound (D). Sodium acetate in ethanol is preferred for conversion of the la,1la-epoxides to the corresponding A compounds.

The compounds of Formula D having the progesterone side chain, i.e., Z: (a)

are converted to the corresponding 4,17(20) [cis] -pregnadien-2l-oic acid lower-alkyl ester in the manner described in U.S. Patent 2,790,814 for the conversion of ll-ketoprogesterone to 3,11-diketo-4,17(20)-pregnadien-2l-oic acid methyl ester, i.e., the selected lla-hydroxyprogesterone is reacted with more than two molar equivalents each of an alkyl die-ster of oxalic acid, preferably methyl or ethyl oxalate, and a base, preferably sodium methoxide or ethoxide or potassium tertiary butoxide, to produce the alkali-metal dienolate of the corresponding 2,2l-dialkoxyoxalyl-llu-hydroxyprogesterone. This compound, or the free enol prepared by reaction of the alkali-metal dienolate with acetic acid, is then trihalogenated with chlorine or bromine, preferably the latter, to produce the corresponding 2,2l-dialkoxyoxalyl-2,2l,2l-trihalo-l lot-hydroxyprogesterone. This compound rearranges with strong base, e.g., an alkali-metal alkoxide, in the presence of an alkanol, e.g., sodium methoxide in methanol or sodium ethoxide in ethanol, to produce the corresponding 2-halo- 11a hydroxy 3-keto-4,l7(20)-pregnadien-21-oic acid alkyl ester. The 2-halo group is removed by zinc and acetic acid or other halogen removing agent to produce the corresponding 11a hydroxy 3-keto-4,l7(20) [cis]- pregnadien-Zl-oic acid alkyl ester which is then ketalized at the 3-position by reaction with an alkylene glycol, e.g., ethylene glycol in the presence of p-toluenesulfonic acid, to produce the corresponding 3-alkylene ketal which can be converted -to the corresponding compounds represented by Formula D in which Z: (17) 1A if] e QUE,

B. it

wherein Z selected from the group consisting of and and R, R and R have the same meanings as previously given. For example, the selected compound of Formula IE is oxidized at the ll-position' with an oxidizing agent, I

PREPARATION 1 11a-hydroxy-I6/3-methylprogester0ne To 16.6 1. of a fermentation medium consisting of 1.2% corn steep solids and 2% Cerelose glucose and adjusted to a pH of 4.8 to 5.0 was added an inoculum of Rhizopus nigricans (A.T.C.C. 6227b) and the medium incubated for 24 hours at a temperature of 28 C. with a rate of aeration of 5% air by volume per minute. To this medium was added 5 g. of 16,3-methylprogesterone dissolved in 35 ml. of acetone. After an additional 24 hours, of incubation under the same conditions, the mycelium was filtered, washed twice, each time with a volume of acetone approximately equal to the volume of the mycelium and then twice with similar portions of methylene chloride. The combined extracts were added to the beer filtrate and the whole was extracted successively with 2 one-half by volume portions of methylene chloride and then with 2 one-fourth by volume portions of methylene chloride. These extracts were Washed with 2 one-tenth by volume portions of 2% aqueous sodium bicarbonate and then with 2 one-tenth by volume portions of water. The methylene chloride extracts were then dried and the solvent removed by distillation. The residue was dissolved in 250 ml. of methylene chloride and chromatographed over a 500 g. column of magnesium silicate (Florisil). The column was developed with 5 l. of methylene chloride, 5 l. of hexanes (Skellysolve B) plus 5% acetone, 1. of hexanes plus 10% acetone, 5 l. of hexanes plus 25% acetone and 2 l. of acetone. The last 7 l. of hexanes plus 10% acetone, the hexanes plus 25 acetone and the first acetone eluates were combined, freed of solvent, redissolved in methylene chloride and rechromatographed over 400 g. of magnesium silicate. The column was developed with 8 1. of hexanes plus 10% aceton, 8 l. of hexanes plus acetone, 4.1 of hexanes plus acetone, 4.1 of hexanes plus acetone and 2,400 ml. of acetone, in that order. The residues from the hexanes plus 10% acetone recrystallized from ethyl acetate to give 11a-hydroxy-l6fl-methylprogesterone, a light colored crystalline solid.

PREPARATION 2 Methyl-11 a-hydr0xy-16a-m ethyl-4,1 7 (20) [cis] pregnadien-3-0ne 21-0ate A solution of 2.00 g. of 11a-hydroxy-16a-methy1- progesterone in dry tertiary butyl alcohol was warmed to about fifty degrees and stirred under nitrogen. To the solution was added 3.2 ml. of ethyl oxalate and 3.03 of a 25% methanolic sodium methoxide solution. A precipitate of the sodium dienolate of 2,2l-diethoxyoxalyl- 1la-hydroxy-l6a-methylprogesterone appeared almost immediately.

The mixture was stirred for twenty minutes after which a cooled solution of 0.98 g. of anhydrous sodium acetate and 0.84 ml. of acetic acid in 40 ml. of methanol was added, thus producing the free dienol. The solution was cooled .to zero degrees centigrade and then treated dropwise with a cold solution of 2.0 grams of bromine in methanol over a period of ten minutes. There was thus produced 2,21,2l-tribromo-2,2l-diethoxyoxalyl-l1w hydroxy-16u-methylprogesterone.

The cooling bath was removed and to the solution was added 5.72 g. of a 25% 'methanolic sodium methoxide solution. The stirring was continued for 2.5 hours. There was thus produced methyl 2-bromo-lla-hydroxy- 16m-methyl-4,17(20)-[-cis]-pregnadien-3-one 21-oate.

To the resulting solution was then added 5 ml. of acetic acid and 1.0 g. of zinc dust and stirring was continued for 30 minutes. The mixture was diluted with water and solids were filtered and the filtrate extracted thoroughly with methylene chloride. The extract was dried with sodium sulfate and evaporated. The residue was dissolved in methylene chloride and chromatographed over a 200 g. column of magnesium silicate (Florisil). The column was developed with hexanes (Skellysolve B) containing increasing proportions of acetone to give methyl 4,17 (20)-[cis]-pregnadien-3-one 21-oate, a light colored crystalline solid which can be further purified by recrystallization from a suitable organic solvent, e.g., methanol.

In the same manner substituting as starting material 11a-hydroxy-l6fl-methylprogesterone, or Ila-hydroxy- 6amethylprogesterone in place of 11a-hydroxy-l6amethylprogesterone, Preparation 1 is productive of methyl 11oz hydroxy 16,8-methyl-4,17(20) [cis]-pregnadien-3- one 2l-oate and methyl 11a-hydroxy-6a-methyl- 4,l7(20) [cis]-pregnadien-3-one 2l-oate, respectively.

In the same manner, other esters are prepared wherein the ester is ethyl, propyl, butyl, etc., by replacing the sodium methoxide in methanol by the selected alkalimetal alkoxide in an alkanol.

PREPARATION 3 1 7: 20,20 21-bism ethylenedioxy-I I/S-hydroxy-I 613- methyl-4-pregrzen-3-0ne To a stirred solution of 7.5 g. of 16,8-methylhydrocortisone in methylene chloride at about 25 C. is added a solution premixed at 0 C. of ml. of low-methanol content formaldehyde (37% aqueous solution) and 110 ml. of concentrated hydrochloric acid. The reaction mixture is stirred at about 25 C. for approximately 20.

thus obtained is triturated with ether to yield 17:20,20:21-

bismethylenedioxy 1lfl-hydroxy-l6B-methyl-4-pregnen- 3-one, a light colored crystalline solid.

In the same manner, substituting as the starting material, 6a-methylhydrocortisone, Preparation 4 is productive of 17:20,20:ZPbismethyIenediQXy-I1B-hydroxy-.

6m-methyl-4-pregnen-3 -onc.

PREPARATION 14 1 1 a-hydroxy-I 6fi-methylprogesterone 3,20-bis(ethylene ketal) A solution of 10 g. of 1lot-hydroxy-l6 3-methylprogesr terone, 1 g. of para-toluenesulfonic acid in 1000 ml. of.

benzene and ml. of ethylene glycol was refluxed for 6 hours using a water trap to remove the water formed in the reaction. The solution was cooled, .water was added and the aqueous layer was separated and extracted with ether and the ether extracts added to the organic layer. The combined organic layers were successively washed with 5% sodium bicarbonate solution, saturated sodium chloride solution, water and then dried over sodi-. The solvents were removed by distillation and the thus-obtained residue. was recrystallized fromum sulfate.

methanol to give 11ahydroxy-l6,8-methylprogesterone 3,20-bis-(ethylene ketal) In the same manner, substituting as starting material in Preparation 3,

17: 20,20: 2l-bismethylenedioxy-1 1 fi-hydroxy-4-pregnen- 3-one,

1 1 a-hydroxyl 6a-methyl- The combined methyl- 17 20,20 21-bismethylenedioxy-1 1 ,B-hydroxy-6a-methyl- 4pregnen-3 -one,

17 I 20,20 2 l-bismethylenedioxy-l IB-hydroxy-l 6a-n1et-hyl- 4-pregnen-3-one,

17 20,20 21-bismethylenedioxy-l 1 B-hydroxy-l 6fi-methy1- 4-pregnen-3-one,

1 la-hydroxy-4-androstane 3 l7-dione,

methyl 1 1a-hydroxy-6a-methyl-4, 17 (20) [cis] pregnadien-3-one-2 l-oate,

methyl 1 1a-hydroxy-16a-methyl-4, 17 (20) [cis] pregnadien-3-one-2Loate or methyl 1la-hydroxy-l6flmethyl-4,l7(20) [cis]- pregnadien-3 -one-2l-oate is productive of 17:20,

20 :21-bismethylenedioxy-1 1,8-hyd-roxy-4-pregnen-3 -one ethylene ketal,

17 20,202 l-bismethylenedioxy-l lB-hydroxy-6a-methyl- 4-pregnen-3-one ethylene ketal,

17 20,20: 2 l-bismethylenedioxy- 1 1,8-hydroxy- 1 6a-methyl- 4-pregnen-3-one ethylene ketal,

17 20,20 2l-bismethylenedioxy-1 15-hydroxy-16B-methyl- 4-pregnen-3 -one ethylene ketal,

11a-hydroxy-4-androstane-3,17-dione bis ethylene ketal,

methyl 1 1a-hydroxy-6a-methyl-4, 17 (20) [cis] -pregnadien- 3-one-2l-oate ethylene ketal,

methyl 1 1a-hydroxy-16a-methy1-4,17 (20) [cis]- pregnadien-3 one-21-oate ethylene ketal and methyl 1 la-hydroxy-l 6,8-methyl-4, 17 20) [cis] pregnadien-3 one-21-oate ethylene ketal, respectively.

In the same manner other 3-ketals and 3,20-bis ketals of the above compounds are produced by the reaction of the selected free keto compound with a glycol as hereinbefore described, e.g., propylene glycol, trimethylene glycol, lower-alkyl substituted ethylene glycols or trimethylene glycols and the like, in the presence of an acid catalyst, e.g., paratoluenesulfonic acid, hydrogen chloride, sulfuric acid.

In the same manner, other esters of the 4,17 (20)-pregnadienes can likewise be ketalized at the 3-position.

PREPARATION 6fi-hydroxy-3,5-cyclopregnan-ZO-one (l) Pregnenolone (3B-hydroxy-S-pregnen-ZO-one) (7.8 g.) dissolved in pyridine (100 ml.) was left at room temperature overnight with p-toluene-sulphonyl chloride (7.8 g.). Water was added and the precipitate collected, washed with water and dried. Crystallization from acetone gave pregnenolone p-toluenesulphonate ester, M.P. 147 C.

Pregnenolone p-toluenesulphonate ester (5 g.) was heated with potassium acetate (5.5 g.) in acetone (70 ml.) and water (70 ml.) under reflux for 8 to 18 hours. The reaction mixture was then poured into water and the product extracted with ether containing a little chloroform. The extract was dried and the solvent distilled. The crude product was recrystallized from acetone, yielding 6-hydroxy-3:5-cycl-opregnan-20-one, needles, P.M. 181 C., [m] +123 (c., 0.663 in chloroform).

In the same manner following the above procedure, but substituting as starting material in place of pregnenolone, 16a-methylpregnenolone or 6-methylpregnenolone, Preparation 5 is productive of 6,8-hydroxy-16u-methyl- 3,5-cyclopregnan-20-one and 6B-hydroxy-6a-methyl-3,5- cyclopregnan-ZO-one, respectively.

PREPARATION 6 618,11a-dihydroxy-3,5-cyclapregnan-20-0ne (II) A medium was prepared of 2.5 kg. of cornsteep liquor (60% solids) and 1.25 kg. of commercial dextrose, diluted to 125 l. and adjusted to a pH of about 5.5; 25.0 ml. of lard oil was added as an antifoam preventive. This sterilized medium was inoculated with a 72-hour vegetative growth of Rhizopus nigricdns (ATCC 6227b) and incubated for 72 hours at a temperature of about 28 C. using a rate of aeration of 5 l. per minute at 300 r.p.m.

After 72 hours of agitation, at which time the .pH of the beer was 7.2, a solution of 20 g. of 6,8-hydroxy-3,5-cyclopregnan-20-one (I) in 300 ml. of N,N-dimethylformamide was added to the inoculated medium. After an additional 24-hour period of incubation, the beer and mycelium were separated by filtration. The mycelium was washed with water and the washwater was added to the beer filtrate. The thus-obtained beer filtrate was extracted 4 times with a volume of methylene chloridezethyl acetate (2:1 by volume) equal to one-fourth the volume of the filtrate. The combined extracts were washed with one fourth volume of distilled water and the solvent was removed by distillation to give a crude residue. This residue was taken up in about 700 m1. of acetone and the solution treated with 7.0 g. of activated charcoal and filtered. The solution was then distilled to a volume of about 150 ml. whereupon the product crystallized giving 14.26 g. of 6,8,11a-dihydroxy-3,S-cyclopregnan-ZO-one, M.P. 211.5217. Three recrystallizations from acetone afforded an analytical sample of 6B,11a-dihydroxy-3,5- cyclopregnan-200m, M.P. 211.5-217", moving as a single spot on a Bush system paper chromatognam. The infrared spectrum was consistent with the indicated structure: A 3500, 3430, 1695, 1065, 1050 and 1025 cm.

Analysis.--Calcd. for C H O C, 75.86; H, 9.70. Found: C, 76.02; H, 10.00.

In the same manner substituting as starting material 6fi-hydroxy-16a-methyl-3,5-cyclopregnan 20 one or 6B- hydroxy-6a-methyl-3,5-cyclopregnan-20-one is productive of 65,11a-dihydr0xy 16-methyl-3,5-cyclopregnan-20one and 66,11u-dihydroxy-6a-methyl 3,5 cyclopregnan 20- one, respectively.

PREPARATION 7 66,1 1fi-dihydroxy-3,5-cycl0pnegnan-20-one Following the procedure of Preparation 6 but substituting Cunninghwmellai blakesleena (ATCC 8688A) for Rhizopus nigricans 6,8-hydroxy-3,5-cyclopregnan-20-one is converted to 63,1lB-dihydroxy-3,S-cyclopregnan-ZO- one, M.P. 239-243 0., A 3500, 3400 and 1695 cm.

Analysis.Calcd. for C H O: C, 75.86; H, 9.70. Found: C, 75.68; H, 9.71.

In the same manner, substituting as starting material 6 8-hydroxy-16a-methyl 3,5 cyclopregnan 20 one or 6B-hydroxy-6a-methyl-3,S-cyclopregnan-ZO-one is productive of 65,1lp-dihydroxy-l6a-methyl-3,5 cyclopregnan- 20-one and 6,8,1 1 13-dihydroxy-6a-methyl-3,5-cyclopregnan- 20-one, respectively.

PREPARATION 8 1 I a-hydroxypregnenolone from ethyl acetate-Skellysolve B hexanes gave colorless 11 dihydroxy-6ot-methyl3,5-cyclopregnan-20 one, Preparation 8 is productive of llfi-hydroxypregnenolone, 110chydroxy 16a methylpregnenolone, 1l/3-hydroxy-16amethylpregnenolone, 1la-hydroxy-6-methylpregnenolone and 11'p-hydroxy-6-methylpregnenolone, 3-respectively.

PREPARATION 9 11 fl-hydroxypregnenolone 3-acetate A mixture was prepared containing 1.0 g. of 1113- hydroxypregnenolone, 20 ml. of acetic acid, 5 ml. of acetic anhydride and 0.4 g. of p-toluenesulfonic acid monohydrate. The mixture was allowed to stand overnight at room temperature. An excess of water was then poured into the reaction mixture and the mixture was chilled at 5 C. The precipitate thus obtained was collected on a filter, washed with cold water and dried to give llp-hydroxypregnenolone B-acetate, a light-colored crystalline solid.

In the same manner, substituting llfi-hydroxy-16otmethylpregnenolone or 1lfi-hydroxy-6a-methylpregnenolone as starting material is productive of llfi-hydroxy- 16a methylpregnenolon 3-acetate and 11B-hydroxy-6otmethyl pregnenolone 3-acetate, respectively.

Other 3-acylates of these llfi-hydroxy compounds can be prepared in accordance with the procedure of Exam ple 20, below.

PREPARATION 1O 11 a-hydroxypregnenolone 3-acetate A mixture of 1.0 g. of lla-hydroxypregnenolone in 20 ml. of acetic acid was refluxed for one hour. Water (100 ml.) was then poured into the reaction mixture. The water solution was then extracted with methylene chloride. The methylene chloride extracts were washed with water, dried over sodium sulfate and chromatographed on snythetic magnesium silicate to give 11ahydroxypregnenolone acetate, a light-colored crystalline solid.

In the same manner, substituting Ila hydroxy-16amethylpregnenolone or 110: hydroxy-6-methylpregnenolone as starting material is productive of Ila-hydroxy- 16a methylpregnenolone B-acetate, and l1a-hydroxy-6- methylpregnenolone 3-acetate, respectively.

EXAMPLE 1 10:,11a-epoxyprogesterone bis ethylene ketal A suspension of 5.0 g. of llfl-hydroxyprogesterone bis ethylene ketal and 15.0 g. of ether washed lead tetraacetate in about 1500 ml. of cyclohexane was allowed to stir at reflux for 4.5 hours. The initially brownish mixture gradually became white as the lead tetraacetate was consumed and the resulting white lead diacetate precipitated. The reaction mixture was cooled, filtered, and the filtrate was washed with 300 ml. of 5% solution of sodium thiosulfate, and water. After drying and evaporating to dryness and residue was crystallized from 30 ml. of acetone to give 1.33 g. of 1a,llrx-epoxyprogesterone bis ethylene ketal, M.P. 195-215 An analytical sample, recrystallized from methanol and ethyl acetate, melted at 212-217", [M -31 (dioxane). Infrared spectrum was in agreement with the structure.

Analysis.Calcd. for C H O C, 72.08; H, 8.71. Found: C, 72.06; H, 8.83.

In the same manner, substituting as starting material, llot-hydroxyprogesterone bis ethylene ketal, 113- hydroxy-6-methylprogesterone bis ethylene ketal, lla-hydroxy-16a-methylprogesterone bis ethylene ketal or 11ahydroxy-l6fi-methylprogesterone bis ethylene ketal, Example l is productive of la,l1rx-epoxyprogesterone bis ethylene ketal, la,lla epoxy-6-methylprogesterone bis ethylene ketal, lot,1lu-epoxy-16 -methylprogesterone bis ethylene ketal and 1u,1lot-epoxy-16fi-methylprogesterone bis ethylene ketal, respectively.

A EXAMPLE 2 1a,]1 a-epOxy-S-pregnene-3,20-dione A solution of 730 mg. of 1a,1la-epoxyprogesterone bis ethylene ketal and 5 ml. of l N sulfuric acid in'about ml. of acetone was gently boiled on the steam bath for about 10 minutes. The reaction mixture was then concentrated under a stream of nitrogen until crystallization took place. Water (100 ml.) was added and the product filtered, washed and dried to give 474 mg. of crystals, M.P. 185l95. One recrystallization from ace.- tone gave 377 mg. of 1u,11a-epoxy-5-pregnene-3,20- dione, M.P. 203208. The analytical sample melted at 205208. Infrared spectrum and nuclear magnetic resonance measurements were in agreement with the structure.

Analysis.Calcd. for C H O C, H, 8.59. Found: C, 76.75; H, 8.89.

In the same manner, substituting as starting material 111,1lot-epoxy-6a-methylprogesterone bis ethylene ketal, 1a,11a-epoxy-16a-methylprogesterone bis ethylene ketal or 10:,11ot epoxy-16 8 methylprogesterone bis ethylene ketal, Example 1 is productive of 1a,llu-epoxy-6-methyl- I 5-pregnene-3,20-dione, 1a,1la epoxy-16a-methyl-5-pregnene-3,20-dione and 1a,11 x-epoxy-16/3-methyl 5 pregnene-3,20-dione, respectively.

EXAMPLE 3 1a,]1 a-ep0xy-5-pregnene-3,ZO-diavze One gram of Ila-hydroxyprogesterone bis ethylene ketal was treated with lead tetraacetate in accordance with the procedure of Examplel, above, to give la,l1a epoxyprogesterone bis ethylene ketal. The crude product was treated with 2 ml. of 2 N sulfuric acid in the same manner as described in Example 2, above, to give 0.57 g. of crude 1a,lla-epoxy-5-pregnene 3,20 dione,.

M.P. 170 C. Two recrystallizations from acetone gave 1a,11a-epoxy-5-pregnene 3,20 dione, M.P. 190- 205 C. An analytical sample melted at 205-208 C. The same product was obtained in Example 2 from the llfi-epimer.

EXAMPLE 4 I -dehydro-1 1 tit-hydroxyprogesterone EXAMPLE 5 1 -dehydr0-1 1 int-hydroxyprogesterone A solution of 100 mg. of 1a,1lot-epoxy-5-pregnene3, 20-dione in about 20 ml. of absolute alcohol was prepared by warming. One hundred mg. of potassium acetate was added and the mixture was allowed to stir and reflux for about 16 hours. Water (50 ml.) was added and the solution was concentrated on the steam bath under reduced pressure to about 10 ml. or until crystallization started. After cooling, the solid was isolated to give 71 mg. of product, M.P. -205 After three recrystallizations from acetone-Skellysolve B hexaues and ethyl acetate-Skellysolve B hexanes, 45 mg. of 1-dehydro-11ahydroxyprogesterone, M.P. 226230 was obtained. This was identical to known samples of l-dehydro-llahydroxyprogesterone by mixed melting point and infrared analysis.

In the same manner, substituting as starting material in either Example 4 or 5, 1a,11a-epoxy-6-methyl-5-pregnene-3,20-dione, 1oz, l'lot-epoxy-l6oc-methyl-5-pregnene 3, 20-dione or 101,11a-epoxy-16/3-methyl-5-pregnene-3,20-dione, Examples 4 and 5 are productive of l-dehydro-llahydroxy-6a-methylprogesterone, 1-dehydro-1la-hydroxy- 16a methylprogesterne and l-dehydro-l1u-hydroxy-165- methylprogesterone, respectively.

EXAMPLE 6 1 11,1 1 a-epoxy-S -androstene-3,1 7-di0ne A suspension of 5 g. of 11a-hydroxy-4-androstene-3,17- dione bis ethylene ketal and 15.0 g. of lead tetraacetate in 1500 ml. of cyclohexane is allowed to stir until the reaction is complete (about 6 hrs.). The reaction mixture is then cooled, filtered and the filtrate washed with about 300 ml. of aqueous 5% sodium thiosulfate solution and water, and dried over sodium sulfate. The solution is then evaporated to dryness and the residue thus obtained, is recrystallized from acetone to give 1a,l1u-epoxy-4- androstene-3,17-dione ibis ethylene ketal, a light colored crystalline solid, which is then dissolved in acetone and treated with 5 ml. of 1 N sulfuric acid and heated on a steam bath for a few minutes. The reaction mixture is then concentrated until crystallization occurs. Water, 100 ml., is then added and the product thus obtained is filtered, washed and dried to give 1a,l1a-epoxy-5-androstene-3,l7-dione, a light colored crystalline solid which can be further purified by recrystallization from acetone.

In the same manner, the llfl-epimer can be substituted as starting material in Example 4 to give 1a,l1a-epOXy5- androstene-3,l7-dione.

EXAMPLE 7 Methyl 1 oc,1l a-ep0xy-5,17(20) [cis] -pregnadiene-3- 0ne-21-oate-3-ethylene ketal To a warm solution of 2.64 g. of methyl lla-hydroxy- 5,17(20) [cis]-pregnadien-3-one-21-oate 3 ethylene ketal in about 750 ml. of purified cyclohexane (heating was necessary in order to efiect solution) was added 10 g. of etherwashed lead tetraacetate. The mixture was allowed to stir and reflux for about 6 hours and was then cooled and filtered through Celite. The filtrate was washed with 5% potassium iodide solution, 5% sodium thiosulfate solution, and water, and was dried. Chromatography over Florisil gave a product fraction (761 mg.) eluted with 2.5 and 5% acetone in Skellysolve B hexanes. Crystallization from ether gave 494 mg. of methyl 111,110:- epoxy-5,l7(20) [cis]-pregnadien-3-one2l-oate, MP. 150- 8". The analytical sample melted at 157-60; )t 224 (el0,300).

Analysis.Calcd. for C H O C, 71.97; H, 8.05. Found: C, 72.09; H, 7.91.

In the same manner, substituting as starting material methyl 1 1a-hydroxy-6-methyl-5, 17 (20) [cis] -pregnadien- 3-one-21-oate 3-ethylene ketal, methyl 11a-hydroxy-16amethyl-5,17(20) [cis]-pregnadien-3-one-21 oate 3-ethylene ketal or methyl 11a-hydroxy-16B-methyl-5,17(20)- [cis]-pregnadien-3-one-21-oate 3-ethylene ketal, Example 7 is productive of methyl 1m,11oc-epoxy-6-methyl-5,17- (20) [cis] -pregnadien3 one 21 oate 3-ethylene ketal, methyl 1a,l1a-epoxy-16a-methyl-5,l7(20) [cis] pregnadien-3-one-21-oate 3-ethylene ketal and methyl loz,llot epoxy-16/3-methyl-5,17(20) [cis] -pregnadien 3 one 21- oate 3-ethylene ketal, respectively.

EXAMPLE 8 1 0a,] 1 a-epOxy-ZI -acetoxy-5 ,1 7(20) [cis] -pregnadien-3- one 3-ethylene ketal To a suspension of 1 g. of lithium aluminum hydride in 50 ml. of anhydrous ether was added a solution of 0.5 g. of methyl 1u,1la-epoxy-5,17(20) [cis]-pregnadien-3-one- 21-oate 3-ethylene ketal in 100 m1. of anhydrous ether. The mixture was allowed to stir and reflux for about 1.5 hours and was then cooled, and the excess lithium aluminum hydride decomposed by the careful addition of ethyl acetate followed by water. The organic phase was separated, washed with water, dried and evaporated to dryness to give a residue containing 1u,l1ot-epoxy-21-hydroxy-5,l7(20) [cis]-pregnadien-Z-one 3 ethylene ketal.

The residue, thus obtained, was dissolved in about 5 ml. of acetic anhydride and 5 ml. of pyridine and allowed to stand for about 16 hours at room temperature (about 25 C.). The reaction mixture was then poured into icewater and extracted with ethyl acetate. The extract was washed with 5% sodium bicarbonate solution and water, dried over sodium sulfate and evaporated to dryness. Attempted crystallization of the residue was unsuccessful even after chromatography over synthetic magnesium silicate. The fraction eluted from the column with 5% acetone in hexanes gave 429 mg. of 1a,-l1u-epoxy-21-acetoxy-5,17(20) [cis]-pregnadien 3 one 3-ethylene ketal. Infrared analysis was consistant with the assigned struc ture. The product was used in Example 9 without further purification.

In the same manner substituting as starting material, methyl 10:, l lot-epoxy-6-methyl-5, 17 (20) [cis] -pregnadien 3-one-2l-oate 3-ethylene ketal, methyl la,11a-epoxy-16umethyl-5,17(20) [cis]-pregnadien-3-one-21 oate 3-ethylene ketal, methyl 1oc,1lac-cpOXY-IGB-methYl-S,17(20) [cis]- pregnadien-3-one-21-oate 3-ethylene ketal or other 21- alkyl esters of the named starting materials. Example 8 is productive of 1u,l1u-epoxy-6-methyl-2l-acetoxy-S,17- (20) [cis]-pregnadien-3-one 3-ethylene ketal, 1u,1lu-epoxy-16a-methyl-21 acetoxy 5,17(20) [cis] pregnadien- 3-one 3-ethy1ene ketal and 10t,1Ia-CPOXY-I6B-IHBthYl-21- acetoxy-5,17(20) [cis]-pregnadien-3-one 3-ethylene ketal.

Similarly other Zl-acylates are prepared by esterification of the 21-hydroxy group in accordance with the procedure of Example 11.

Other 3-alkylene ketals of the above-named starting materials can likewise be substituted in place of the 3- ethylene ketals.

EXAMPLE 9 1 0t,11oL-p0Xy-1 7a-hydr0xy-21-acetoxy-5-pregnene- 3,20-di0ne 3-ethylene ketal To a solution of 0.43 g. of la,lla-epoxy-2l-acetoxy- 5,17-(20) [cis]-pregnadien-3-one 3-ethylene ketal in about 25 ml. of t-butyl alcohol and 0.65 ml. of pyridine was added 1.35 ml. of N-methylmorpholine oxide peroxide (2.0 N) followed by 15 mg. of osmium tetroxide. After stirring for 2.5 hours at room temperature, 15 ml. of a 5% solution of sodium hydrosulfite was added followed 15 minutes later by 0.5 g. of magnesol. After an additional 15 minutes, the stirrer was stopped and the mixture was filtered through Celite. The filtrate was concentrated to near dryness under reduced pressure, diluted with water, and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, and evaporated to dryness. Chromatography of the residue over magnesium silicate (Florisil) gave 182 mg. in the product fraction, eluted with 10 and 15% acetone in Skellysolve B hexanes which on crystallization fiom acetone-Skellysolve B hexanes gave 112 mg. of la,1lozepoxy-l7a-hydroxy-2l-acetoxy-5-pregnene-3,20-dione 3- ethylene ketal, M.P. -205. Two recrystallizations from the same solvents did not raise the melting point.

AnaZysis.- Calcd. for c n o c, 67.24; H, 7.67. Found: C, 67.26; H, 8.32.

In the same manner substituting as starting material 1u,11a epoxy 6-methyl-2l-acetoxy-5,17(20) [cis] -pregnadien-3-one 3-ethylene ketal, 1u,11a-6pOXY-160L-H16thyl 21 acetoxy 5,17 (20) [cis] -pregnadien-3-one 3-ethylene ketal, or 141,1lu-epoxy-l6 8-methyl-2l-acetoxy-5,17(20) [cis]-pregnadien-3-one 3-ethylene ketal, Example 9 is productive of 1a,llu-epoxy-6-methyl-17a-hydroxy-21-acetoxy 5-pregnene-3,20-dione 3-ethylene ketal, 1a,11aepoxy 16ot-methyl-17u-hydroxy-2l-acetoxy-5-pregnene- 3,20-dione S-ethylene ketal and 1a,11u-epoxy-16flmethyl 17oz hydroxy-21-acetoxy-5-pregnene-3,ZO-dione 3-ethylene ketal, respectively.

In the same manner, other 21-esters of the above compounds are prepared by substituting as starting material other 21-acylates of the above compounds to produce the corresponding 21-acylate, e.g., 1a,1la-epoxy-17ahydroxy 21 propionoxy-5-pregnene-3,20-dione 3-ethy1- ene ketal, 10:,11a-epoxy-6-methyl-17u-hydroxy-2l-butyroxy-5-pregnene-3,20-dione 3-ethylene ketal, 10:,11aepoxy 1Goa-methyl-17a-hydroxy-21-octanoyloxy-5-pregnene-3,20-dione 3-ethylene ketal and the like.

EXAMPLE 10 10:,11 oz-epoxy-l 70:,21-dihydroxy-5-pregnene- 3,20-dine 3 -ethylene ketal A solution was prepared containing 0.5 g. of la,llcc epoxy 17oz hydroxy-21-acetoxy-5-pregnene-3,20-dione 3-ethylene ketal in methanol. This solution was purged with oxygen-free nitrogen for a period of minutes and then a similarly oxygen purged solution of 0.250 g. of potassium bicarbonate dissolved in 1 ml. of methanol and 1 ml. of water was added. The mixture was maintained for 3 hours in a nitrogen atmosphere, then neutralized with hydrochloric acid, poured into 200 ml. of ice water and the thus-obtained mixture extracted with four 50 ml. portions of methylene chloride. The methylene chloride extracts were combined, washed several times with water, dried over anhydrous sodium sulfate and evaporated to give 1a,1lot-epoxy-17a,2l-dihydroxy- 5-pregnene-3,20-dione 3-ethylene ketal, a light colored crystalline solid.

In the same manner, substituting as starting material 1a,11a epoxy 6-methyl-17-hydroxy-21-acetoxy-5-pregnene-3,20-dione 3-ethylene ketal, 1a,11a-ep0xy-16amethyl 17oz hydroxy-21-acetoxy-5-pregnene-3,20-dione 3-ethylene ketal or 1a,11a-epoxy-l6j3-methyl-17a-hydroxy 21 acetoxy 5-pregnene-3,20-dione-3-ethylene ketal, Example 10 is productive of 10c,1 la-epoxy-6-methyl- 17a,21-dihydroxy-5-pregnene-3,20dione 3-ethylene ketal, 1oz,1lcc epoxy 16oz methyl-17a,21-dihydroxy-5-pregnene-3,20-dione 3-ethylene ketal and 1u,11a-epoxy-16flmethyl-170:,2l-dihydroxy-S-pregnene-3,2O-dione 3-ethylene ketal, respectively.

Other 21-esters can likewise be hydrolyzed to the corresponding 21-free alcohols.

EXAMPLE 11 1 a,I1a-ep0xy-17a-hydroxy-21-acet0xy-5-pregnene- 3,20-di0ne 3 -ethylene ketal A solution of 100 mg. of 1a,11a-epoxy-17a,21-dihydroxy-S-pregnene-3,20-dione 3-ethylene ketal in 1 ml. of pyridine and 1 ml. of acetic anhydride was maintained at room temperature for 17 hours. Crushed ice in water was added and the product thus obtained was extracted with three 10 ml. portions of methylene chloride. The methylene chloride extracts were dried over anhydrous sodium sulfate, evaporated and the residue recrystallized from a mixture of ethyl acetate and hexanes to give 111,11 epoxy 17a-hydroxy-21-acetoxy-5-pregnene-3,20- dione 3-ethylene ketal, identical to the same product prepared in Example 9, above.

In the same manner, substituting as starting material the other 21-hydroxy compounds prepared as listed in the second paragraph of Example 10, Example 11 is productive of 111,110: epoxy--methyl-17u-hydroxy-21- acetoxy-S-pregnene-S,20-dione 3-ethylene ketal, 1a,l1ct epoxy 16oz methyl-l7oc-hydroxy-2l-acetoxy-5-pregnene- 3,20-dione 3-ethylene ketal and 1a,1lu-epoxy-16fi-methyl- 17a hydroxy 21-acetoxy-5-pregnene-3,20-dione S-ethylene ketal, respectively.

Similarly, these 21-hydroxy starting materials can be converted, by esterification of the 21-hydroxy group, e.g., by reaction with the appropriate acid anhydride, acid chloride or bromide, ester by ester exchange, acid in the presence of an esterification catalyst, etc., to other corresponding 2l-acylates, including those wherein the acyl group is the acyl radical of, for example, a loweraliphatic acid, e.g., formic, propionic, butyric, isobutyrie, valeric, isovaleiric, trimethylacetic, 2-methylbutyric, 3- ethylbutyric, hexanoic, diethylacetic, triethylacetic, heptanoic, octanoic, a-etbylisovaleric, a cyclic acid, e.g., cyclopropylideneacetic, a cycloaliphatic acid, e.g., cyclopentylformic, cyclopentylacetic, ,B-cyclopentylpropionic, cyclohexylformic, cyclohexylacetic, S-cyclohexylpropionic, an aryl or alkaryl acid, e.g., benzoic, 2, 3, or 4- methylbenzoic, 2,3-, 2,4-, 2,5-, 2,6- 3,4- and 3,5-di-. methylbenzoic, ethylbenzoic, 2,4,6-trimethylbenzoic, 2,4,6- triethylbenzoic, a-napht'hoic, S-methyl-a-naphthoic, an aralkyl acid, e.g., phenylacetic, phenylpropionic, diphenylacetic, triphenylacetic acid, a dibasic acid (the ester of which can be converted, e.g., to a sodium salt), e.g., succinic acid.

EXAMPLE 12 10:,11 a-epoxy-I 7a-hydroxy-21-acet0xy-5-pregnene- 3,20-di0ne A solution of mg. of 1a,11a-epoxy-17a-hydroxy- 2l-acetoxy-5-pregnene-3,20-dione 3-ethylene ketal in about 20 ml. of acetone and 1.5 m1. of 1 N H sOgwas gently boiled on the steam bath for 10 minutes. (The volume was reduced to about one-half.) The solution was cooled, diluted with 25 ml. of water, concentrated under reduced pressure till the acetone was removed, and cooled in an ice-bath. The resulting solid was filtered oil to give 71 mg. of 1a,l1ot-epoxy-17u-hydroxy-21-acetoxy- 5-pregnene-3,20-dione, M.P. -205. The analytical sample, crystallized from acetone Skellysolve B, melted at 203-8".

Analysis.Calcd. for C H O C, 68.67; H, 7.57. Found: C, 68.99; H, 7.30.

In the same manner, substituting as starting material 10a, 1 la-epoxy-6-methyl17a-hydroxy-21-acetoxy-5- pregnene-3,20-dione 3-ethylene ketal,

10:,11a-epoxy-16u-methyl-17a-hydroxy-21-acetoxy-5- pregnene-3,20-dione 3-ethylene ketal,

1a,1 la-epoxy-16fl-methy1-17a-hydroxy-21-acetoxy-5- pregnene-3,20-dione 3-ethylene ketal or the corresponding 21-free hydroxy compounds prepared in Example 10, above, Example 12 is productive of the corresponding free 3-keto compound,

In the same manner, the other 21-acylates prepared in Example 11 can likewise be converted to the corresponding free 3-keto compounds.

EXAMPLE 13 1 a,11u-epoxy-I7 220,20 21-bismethylenedioxy-4-pregnen- 3-0ne 3-ethylene ketal Substituting 17:30,2O:21 bismethylenedioxydlfl hydroxy-4-pregnen-3-one 3-ethylene ketal as starting material in Example 7 is productive of 1oc,11oc6p0Xy-l7;20, 20:2l-bismethylene-dioxy-4 pregnen 3 one 3 ethylene ketal, a light colored crystalline solid.

In the same manner, 17:20,20:ZI-bismethylenedioxy-(S- methyl-1lp-hydroxy=4=pregnen-3-one 3 ethylene ketal,

1 7 17 20,20 2 l-bismethylenedioxy-l 1B-hydroxy-16amethyl-4-pregnen-3-one 3-ethylene ketal and 17 :20,20: 2l-bismethylenedioxy-1 1 B-hydroxy-l 613- methyl-4-pregnen-3-one 3-ethylene ketal are converted to 111,1la-epoxy-6-methyl-17:20,20:2lbismethylenedioxy-4-pregnen-3-one 3-ethylene ketal, 1oz, 11u-epoXy-16m-methyll7 :20,20:21 bismethylenedioxy 4-pregnen-3-one 3-ethylene ketal, and 1u,11a-epoxy-16fimethyl 17:20,20:21 bismethylenedioXy-4-pregnen-3 one 3-ethylene ketal, respectively.

In the same manner, substituting as starting material in Example 12, the other 6 and 16-substituted bismethylenedioxy compounds prepared and listed in the second paragraph of Example 13, is productive of the corresponding free 3 keto-A -compounds, 111,110; epoxy-6- methyl 17 20,20 21 -bismethylenedioxy-S-pregnen-3-one, 141,11a-epoxy-16u-methyl-17:20,20z21 bismethylenedioxy-5-pregnen-3-one and 104,11u-epoxy-16fl-methyl-17:20, 20:21-bismethylenedioxy-S-pregnen-B-one, respectively.

EXAMPLE 15 110a,] 711,21 -1rihydr0xy-1 ,4-pregnadiene-3,20-dine 21 acetate A solution of 100 mg. of 101,11a-epoxy-17a-hydroxy21- acetoxy--pregnene-3,ZO-dione in absolute alcohol is prepared by warming. One hundred mg. of potassium acetate is added and the mixture is allowed to stir and reflux until the epoxide ring cleavage is complete. Water (about 50 ml.) is then added and the mixture is concentrated on the steam bath under reduced pressure to about 10 ml. or until crystallization starts. The mixture is then cooled and the solid isolated to give 11a,17u,21-trihydroxy-1,4- pregnadiene-3,20-dione 21-acetate, a light colored crystalline solid which can be further purified by recrystallization from a suitable solvent, e.g., aoetonezhexanes.

In the same manner, substituting as starting material,

1u,1 1m-epoxy-6-methyl-17a-hydroxy-2 l-acetoxy-S- pregnen-3,20-dione,

141,1 la-epoxy-l 6a-methyl-17a-hydroxy-2 l-acetoxy-S- pregnen-3,20-dione,

1a,1 1a-epoxy-16B-methyl-17a-hydroxy-2l-acetoxy-ipregnen-3,20-dione,

1u,11a-epoxy-17a,2 1-dihpdroxy-5-pregnen-3,2'0-dione,

112,1 1a-epoxy-6-methyl-17a,2l-dihydroxy-S-pregnene- 3,20-dione,

Inc, 1 1u-epoxy-16u-methyl-17u,2l-dihydroxy-S-pregnehe- 3,20-dione,

10:,11 a-epoxy-l6;3-methyl-17 1,21-dihydroxy-5-pregnene- 3,20-dione or other 21-acylates of these compounds, Example 15 is productive of 6a-methyl-11a,17a,21-trihydroXy-1,4pregnadiene-3,20-

dione 21-acetate,

lfiu-methyl-l 1a,17a,21-trihydroxy-1,4-pregnadiene-3 ,20-

dione 21-acetate,

16,8-methyl-1 1oz, 17a,21-trihydroxy-1 ,4-pregnadiene-3,20-

dione 21-acetate,

1 1a,170:,21-trihydroxy-1,4-pregnadiene-3,20-dione,

6a-methyl-11m,17,21-trihydroxy-1,4-pregnadiene-3,20-

dione,

16u-methyl-11a,17a,21-trihydroxy-1,4-pregnadiene-3,20-

dione,

16B,methyl-l 1a,17a,2l-trihydroxy-1,4-pregnadiene-3,20-

dione or other 21-acylates thereof, respectively.

. EXAMPLE 16 1 1 u-hydroxy-l 7:20,20:21 -bismethylenedi0xy 1,4- pregnadien-3-0ne A solution of 100 mg. of 1u,11u-epoxy17:20,20:21 bismethylenedioxy 5-pregnene-3-one in absolute alcohol is prepared by warming. One hundred mg. of potassium acetate is added and the mixture is allowed to'stir'and reflux until the epoxide ring cleavage is complete. Water (about 50 ml.) is then added and the mixture is concentrated on the steam bath under reduced pressure to about 10 ml. or until crystallization starts. The mixture is then cooledand the solid is isolated to give lla-hydroxy l7z20, 20:21 bismethylenedioxy-1,4-pregnadien-3-one, a light colored crystalline solid which can be further purified by recrystallization froma suitable solvent, e.g., acetonehexanes. V

In the same manner, substituting as starting material,"

10:,1 1a-epoxy-6-methyl- 17 120,20 2 1 -bismethylenedioxy- 5-pregnen-3-one,

10:,11 a-epoxy-16a-methyl-17: 20,205 ZI-bismethylenedioxy-S-pregnen-S-one or 101,1 1m-epoxy-16B methyl-17 20,20 2 l -bismethylenedioXy-5-pregnen-3-one,

is productive of 6-me'thyl-1 1u-hydroxy-17 20,20 21-bismethylenedioxy-1,4-pregnadien-3-one,

dioxy-1 ,4-pregnadien 3 one and 110: hydroxy-16;8-methyl-17220,20:21 bisrnethylenedioxy-1,4-pregnadien-3-one, respectively.

EXAMPLE l7 v 1a,11 a-epoxypregnehol one acetate To a hot solution of 0.75 g.- of llu-hy'droxypregnenolone 3-acetate in 3.00 ml. of purified cyclohex-ane was added 4 g. of ether washed lead' tetraacetate. The mixture was allowed to stir and reflux for about 4 hours and was then cooled and filtered through diatomaceous earth (Celite). The filtrate was washed with 5% potassium iodide solution, 5% sodium thiosulfate solution, and water was dried over anhydrous sodium sulfate. Chromatography of the solution over'100 g. of Florisil resulted in the product fraction being eluted with 7.5% acetone in Skellysolve B. Recrystallization of this material from acetone 240 mg. of 1a,11u-epoxypregnenolone acetate, M.P. ISO-157. An analytical sample melted at 152157; [04] -20 (CHCI Analysis.Calcd. for C H O C,74.16; H, 8.66. Found: C, 73.55; H, 8.62.

In the same manner, substituting as starting material, 1la-hydroxy-l6u-methylpregnenolone 3-acetate or 1101- hydroxy-6-methylpregnenolone-3-acetate, Example 17. is productive of 111,1 1a epoxy-1u-methylpregnenolone acetate and 1a,11a-epoxy-6-methylpregnenolone acetate, respectively.

EXAMPLE 18 10;,11 a-epoxypregnenolone acetate Treatment of 0.96 g. of llfi-hydroxypregneriolone 3- acetate with 7 g. of lead tetraacetate for 15 hours as given above for the lloc-hYdI'OXY epim'er, gave 113 mg. of 10,11oL-6POXY pregnenolone acetate, M.P. 142-155. The analytical sample melted at 149-455; [a1 17 (CHCI Analysis.-Calcd. for C H O C, 74.16; H, 8.66'.

' Found: C, 74.36; H, 9.06.

There was no depression in melting point when the two epoxides from Examples 16 and 17 were mixed and th infrared curves of the two were identical.

In the same manner, substituting as starting material, 1lfl-hydroxy-l6a-methylpregnenolone acetate, or 11B-hydroXy-6-methylpregnenolone 3-acetate, Example 18 is 19 productive of la,lla-epoxy-l6a-methylpregnenol0ne acetate and 111,1la-epoxy-6-methylpregnenolone acetate, respectively.

EXAMPLE 19 1a,11a-epoxypregnenol0ne 100 mg. of 1u,l1a-epoxypregnenolone acetate, 1.0 ml. of l N sodium hydroxide solution and ml. of methanol was refluxed for about minutes under nitrogen, then neutralized with hydrochloric acid, poured into 50 ml. of ice water and the thus-obtained mixture extracted with three 10 ml. portions of methylene chloride. The extracts were combined, washed with water, dried over sodium sulfate and evaporated to give 1a,1la-epoxypregneno lone, a light colored crystalline solid.

In the same manner, substituting la,lla-epoxy-l6amethylpregnenolone acetate or 1a,l1a-epoxy-6-methylpregnenolone acetate as the starting material, Example 19 is productive of 10:,1la-epoxy-l6a-methylpregnenolone and a,l1a-epoxy-6-methylpregnenolone, respectively.

EXAMPLE 10;,11 a-epoxypregnenolone acetate A solution of 100 mg. of la,lla-epoxypregnenolone in 1 ml. of pyridine and 1 ml. of acetic anhydride was maintained at room temperature for about 17 hours. Crushed ice and water was added and the 10:,11a-6POXY- pregnenolone acetate thus obtained was extracted with three 10 ml. portions of methylene chloride. The methylene chloride extracts were dried over anhydrous sodium sulfate, evaporated and the residue recrystallized from a mixture of ethyl acetate and hexanes to give la-IIOL- epoxypregnenolone acetate, identical to the same product obtained in Example 17.

In the same manner, substituting 1a,lla-epoxy-l6amethylpregnenolone or 101,11a-epoxy-6-methylpregnenolone as starting material, Example 20 is productive of 1a,11a-epoxy-l6u-methylpregnenolone acetate and lot, 11a-epoxy-6-methylpregnenolone acetate, respectively.

Similarly, 1a,1lm-epoxypregnenolone, b llot-epoxy- 16a-methylpregnenolone and 1a,1la-epoxy-6-methylpregnenolone are converted, by esterification of the 3-hydroxy group, e.g., by reaction with the appropriate acid anhydride, acid chloride or bromide, ester by ester exchange, acid in the presence of an esterification catalyst, to other la,lla-epoxypregnenoloue acylates, 10:,11u-6P0XY-16amethylpregnenolone acylates and la,lla-epoxy-6-methyl pregnenolone acylates, including those wherein the acyl group is the acyl radical of, for example, the acids listed in Example 11.

The lead tetraacetate used in the above examples was triturated 4 times with anhydrous ether before using to remove acetic acid which is present in the material as purchased.

I claim:

1. A compound selected from the formulae:

boxylic acid containing from 1 to 12 carbon atoms, inclusive, and Z is selected from the group consisting of:

CH; GHzOR: 0-0112 (1:) 47:0 ([1) =0 and (c) H1O 1H OH 0- H2O OH:

wherein R and R are selected from the group consisting of hydrogen and methyl in which when R is methyl R is hydrogen, R is an alkylene radical containing'from 2 1 to 8 carbon atoms, inclusive, and the attaching oxygen to carbon bonds are separated by a chain of at least 2 but not more than 3 carbon atoms, and Z is selected from the group consisting of:

CH; COOR 0-OH1 f 0 H and (4:) mo

0/ 7 o-o-o 0 l 011. OH

in which R is defined as above and R is lower-alkyl radical, containing from one to 8 carbon atoms, inclu-.

sive.

8. Methyl 1u,-11a-epoxy-5,17(20)[cis]-pregnadien-3- one-2l-oate-3-ethylene ketal.

9. A process for the production of 10:,11a-CPOXY steroids of the androstane and pregnane series which com-1 prises oxidizing an ll-hydroxy steroid selected from the group consisting of the androstane and pregnane series, containing no other free hydroxyl group with lead tetraacetate to produce the corresponding 1a,11a-epoxy steroid.

10. A process for producing A -1la-hydroxy steroids of the androstane and pregnane series which comprises treating a A -la,11a-epoxy-3-keto compound selected from the group consisting of the androstane and pregnane series with a member of the group consisting of an acid and a base to produce the corresponding A -l lot-hydroxy steroid.

11. A process for the production of a compound of the formula:

wherein R and R are selected from the group consisting of hydrogen and methyl in which when R is methyl R is hydrogen, R is an alkylene radical containing from 2 to 8 carbon atoms, inclusive, and the attaching oxygen to carbon bonds are separated by a chain of at least 2 but not more than 3 carbon atoms, and Z is selected from the group consisting of:

in which R is defined as above and R is a lower-alkyl radical containing from 1 to 8 carbon atoms, inclusive which comprises: oxidizing a compound of the formula:

wherein R, R R and Z are defined as above and X is selected from the group consisting of the u-hydroxymethylene radical and the ,B-hydroxymethylene radical, with lead tetraacylate to produce the corresponding 1a., lla-epoxide.

12. A process for the production of 1u,11u-epoxyprogesterone bis ethylene ketal which comprises: oxidizing lla-hydroxyprogesterone bis ethylene ketal with lead tetraacetate to produce 1a,lla-epoxyprogesterone bis ethylene ketal.

13. A process for the production of 1a,1la-epoxy-4- androstene- 3,17-dione bis alkylene ketal which comprises: oxidizing a compound selected from the group consisting of 11fi-hydroxy-4-androstene-3,17-dione bis alkylene ketal and 11u-hydroxy-4-androstene-3,l7-dione bis alkylene ketal with lead tetraacylate to produce ,110t-8POXY- 4-androstene-3,17-dione bis alkylene ketal.

14. A process for the production of methyl-la,1laepoxy 5,17()[cis]-pregnadiene-3-one-2l-oate 3-ethylene ketal which comprises: oxidizing methyl lla-hydroxy- 5,l7(20)-[cis]-pregnadien-3-one-2l-oate 3-ethylene ketal with lead tetraacetate to produce the corresponding 1:1, Ila-epoxy compound.

15. A process for the production of a compound of the formula:

wherein Ac is the acyl radical of an organic carboxylic acid, R and R are selected from the group consisting of hydrogen and methyl, in which when R is methyl R is 2i hydrogen, which cornprises: oxidizing a compound of the formula:

wherein Ac and R and R are defined as above and X is selected from the group consisting of the u-hydroxymethylene radical and the ,d-hydroxymethylene radical, with lead tetraacylate to produce the corresponding 10L, Ila-epoxy compound.

16. A process for the production of a compound of the formula:

H0--( ]-wR wherein R and R are selected from the group consisting of hydrogen and methyl in which when R is methyl R is hydrogen and Z is selected from the group consisting of in which R is selected from the group consisting of hydrogen and the acyl radical of an organic carboxylic acid, which comprises treating a compound of the formula:

23 24 20. A compound selected from the group consisting of References Cited by the Examiner a compound of the formula P a 2,602,769 7/1952 Murray et a1. 195-51 2,838,501 6/1958 Campbell et a1. 260239.55

OTHER REFERENCES Kalvoda et 21.: Helv. Chim. Acta, vol. 44, pages 186- 198, Feb. 1, 1961. m LEWIS GOTTS, Primary Examiner.

MORRIS LIEBMAN, IRVING MARCUS, Examiners.

H. A. FRENCH, Assistant Examiner.

and the corresponding 3,20-bisethylene ketal thereof. 

1. A COMPOUND SELECTED FROM THE FORMULAE: 